Mitral Annular Disjunction: Separating the Wheat from the Chaff

Mitral annular disjunction (MAD) has evolved from an obscure footnote to a sign of imminent sudden cardiac death and back to a universal finding in a span of a decade.^1,2 As is often the case, the truth and the devil are in the details. MAD was first observed in autopsies and later in echocardiography of subjects with mitral valve prolapse (MVP). When the entire circumference of the mitral annulus was evaluated by CT or cardiac MRI, segments of MAD were found to be present in the vast majority of individuals.¹ Yet, inferolateral MAD was much less common and strongly associated with MVP and left ventricular fibrosis. Therefore, in the context of MVP and arrhythmia, one should only consider inferolateral MAD.

As with many anatomical variants before MAD, we have transitioned from severe underdiagnosis due to lack of awareness of this entity to increasing overdiagnosis, as Katritsis and Anderson argued recently in this journal.³ This may occur, particularly on cardiac MRI, when mitral leaflet curling is present, creating the illusion of a systolic separation from the annulus in a phenomenon called pseudo-MAD. True MAD diagnosis requires a careful analysis of the images with identification of the annular plane and the correct insertion of the posterior leaflet. Even when correctly diagnosed, inferolateral MAD is common among subjects with MVP and even more so in myxomatous degeneration of the mitral valve. The existence of isolated inferolateral MAD remains heavily contested with no clear resolution at present. Regardless, when observed alongside MVP, MAD has been consistently shown to be associated with an increased rate of sustained ventricular arrhythmia but not necessarily an increased risk of death.⁴

The importance of MAD in the complex of MVP risk stratification should not be overemphasised. As MAD is a common feature of myxomatous MVP, it may be considered as one additional risk factor of sustained arrhythmia rather than a deterministic marker of sudden cardiac death. Most people with MVP and MAD will never experience significant arrhythmia in their lifetime. However, when MAD is accompanied by left ventricular (LV) dysfunction, mitral regurgitation, T-wave inversions, rapid non-sustained ventricular tachycardia, LV fibrosis and/or history of unexplained syncope, the risk of life-threatening arrhythmia is significantly higher. There are preliminary data suggesting that the extent of MAD, as defined by its length, further increases the risk of arrhythmia, but this is yet to be supported by robust evidence. A recent study has suggested the association between MAD length and arrhythmic risk may be stronger in males compared to females.

The mechanistic importance of MAD is widely debated. It is hypothesised that MAD causes paradoxical systolic annular dilation and abnormal motion termed curling. This is believed to cause myocardial stretch in the LV inferobasal segment and excessive papillary muscle traction, leading to hypertrophy and fibrosis.⁵ The area of fibrosis and its border zone may support re-entrant circuits explaining the higher incidence of monomorphic ventricular tachycardia rather than ventricular fibrillation in patients with MAD. Recent work summarising the experience with catheter ablation reports a higher rate of ventricular tachycardia (VT) inducibility, complex fractionated signals and a significant proportion of VT circuits mapped within the MAD region.⁶ It has been suggested that empiric substrate modification targeting the MAD region may reduce arrhythmia recurrence. The predominance of spontaneous monomorphic ventricular tachycardia, as well as higher rates of VT inducibility in patients with MAD suggest a possible role for programmed ventricular stimulation as part of the risk stratification process in this subgroup.⁷

MAD has been treated by cardiac surgeons long before it was systematically recognised by the wider community of cardiologists. Elimination of MAD has been a part of mitral valve repair surgery for years. However, recent studies show that the increased arrhythmic risk, compared to cases without MAD undergoing mitral valve replacement (MVR), persists.⁸ This suggests the electrical remodelling and arrhythmogenic substrate may be partly or fully irreversible. Further, it is increasingly recognised that the arrhythmogenic MVP/MAD spectrum is often accompanied by a ventricular myopathy above and beyond the mitral valve apparatus. Such a myopathic substrate obviously remains unaffected by any surgical (or ablative) interventions and may continue to harbour arrhythmic risk. It is worth noting that while transcatheter edge-to-edge repair of the mitral valve reduces regurgitation, it does not correct MAD.

Lastly, MVP should be considered a progressive degenerative condition, although the exact nature and trajectory of its time-dependent structural and electrical remodelling remain incompletely defined. The most established dynamic component of the MVP phenotype is mitral regurgitation, which worsens over time in a clinically meaningful minority of patients, and severe regurgitation is associated with excess mortality, including arrhythmic death. Importantly, regurgitation severity does not always correlate with the presence or extent of MAD. Moreover, sudden cardiac death in the arrhythmic MVP phenotype can occur in individuals with mild or even absent regurgitation and preserved left ventricular systolic function.

MAD is real and relevant. Nonetheless, its notoriety risks outpacing the strength of the evidence supporting its independent prognostic value. MAD is a heterogeneous anatomic finding that exists along a spectrum of morphological, electrical and clinical vulnerability. The diagnosis of MAD remains nuanced, and awareness of the limitations of each imaging modality is paramount. Several critical knowledge gaps persist, such as the biological basis of MAD, the clinical relevance of MAD length and potential for progression, and whether interventions, such as programmed ventricular stimulation, catheter ablation and surgery, meaningfully alter outcomes, to name a few. In the midst of the artificial intelligence boom, deep learning predictive analytics of the electrocardiographic and imaging signatures of MAD may help piece together the remaining elements of this complex puzzle, though that remains to be seen. Until then, caution and common sense are advised.